Anti-secretory and anti-proliferative actions of next-generation dual subtype 2 and 5 somatostatin receptor ligands in neuroendocrine tumor models.

Introduction: First-generation somatostatin receptor ligands (SRLs) mainly target SSTR2, whereas neuroendocrine tumors (NETs) often express multiple SSTR subtypes, frequently SSTR5. Dual SSTR2/SSTR5 targeting may enhance anti-hormonal and antiproliferative effects. We evaluated five novel dual SSTR2/SSTR5 agonists (SMTR-001 to SMTR-005) in preclinical NET models to assess their anti-secretory and anti-proliferative effects in representative preclinical NET models. Methods: The human insulinoma-derived NT-3 cell line and the murine AtT-20 corticotroph cell line, both expressing SSTR2 and SSTR5, were treated with 1-50 nM of the novel SRLs or reference agents (octreotide, pasireotide). Insulin and ACTH secretion were quantified by ELISA and cell viability was measured after 72 h (AtT-20) or 5 days (NT-3). A putative lead compound, SMTR-002, was further tested in 3D spheroid cultures of NT-3 cells. Intracellular cAMP modulation was evaluated after forskolin stimulation in AtT-20 cells. Results: In NT-3 cells, all dual SRLs inhibited insulin secretion (-65% to -95%), with SMTR-002, SMTR-004, and SMTR-005 showing significantly greater inhibition than octreotide at 10 nM. Each compound also reduced cell proliferation (-30% to -44%). In 3D cultures of NT-3 cells, SMTR-002 reduced insulin secretion to a degree comparable to octreotide but, unlike octreotide, significantly decreased cell proliferation. In AtT-20 cells, four novel SRLs significantly reduced ACTH secretion (-11% to -69%), with SMTR-001 and SMTR-004 showing efficacy comparable to pasireotide. SMTR-002 and SMTR-003 demonstrated the greatest antiproliferative effects (-53% and -48% at 10 nM). In AtT-20 cells, SMTR-002 also suppressed forskolin-induced cAMP accumulation more strongly than reference SRLs. Conclusion: Dual SSTR2/SSTR5 agonists exhibit antisecretory and antiproliferative activity in NET models that was similar or even superior to reference SRLs. These findings support their further development as next-generation SRLs for SSTR2/5-expressing tumors.